Effectiveness, tolerability, and safety of subcutaneous methotrexate in early rheumatoid arthritis: A retrospective analysis of real-world data from the St. Gallen cohort

Abstract

Introduction

Methotrexate (MTX) is the cornerstone of rheumatoid arthritis (RA) treatment. Recently updated recommendations by the European League Against Rheumatism (EULAR) show MTX as an important part of the first-line strategy in patients with active RA. The study presented here aimed to assess the clinical effectiveness and tolerability of subcutaneous (SC) MTX among patients with RA.

Methods

Patients with RA who were naïve at baseline to both conventional and biologic disease-modifying antirheumatic drugs, fulfilled the American College of Rheumatology/EULAR 2010 criteria, and had one or more follow-up visits were selected through sequential chart review for analysis of retrospective data. Patients received SC MTX at varying doses (10–25 mg per week). The primary end point was a change in the Disease Activity Score including 28 joints (DAS28); secondary end points included time to employment of the first biologic agent and cumulative MTX doses.

Results

Overall, 70 patients were in follow-up for a mean of 1.8 years after initiating SC MTX treatment. During this time, 37 (53%) remained on SC MTX without any biologics (MTX-only) and 33 (47%) required the addition of a biologic therapy (MTX-biol). Biologic therapy was required after a mean ± SD of 387 ± 404 days. Mean weekly MTX doses were 17.4 mg for patients in the MTX-only group and 19.1 mg for patients in the MTX-biol group. Mean baseline DAS28 were similar for patients in the MTX-biol and MTX-only groups (4.9 and 4.7, respectively). Both low disease activity state (LDAS) and remission were achieved by slightly fewer patients in the MTX-biol than MTX-only groups (LDAS, 78.8% vs 81.1%; remission, 69.7% vs 75.7%). Over the full course of the study period, SC MTX was discontinued in 32 patients (46%). Among those who discontinued, the most common reasons were gastrointestinal discomfort (n = 7), lack of efficacy (n = 7), and disease remission (n = 3). Severe infections occurred in 3 patients in the MTX-biol group and 3 patients in the MTX-only group.

Conclusions

SC MTX is a safe and effective treatment option for patients with RA. SC MTX resulted in high rates of remission and LDAS in early disease, over prolonged periods of time, it, therefore, may extend the time before patients require initiation of biologic therapy.

Introduction

Methotrexate (MTX) has been the cornerstone of treatment for rheumatoid arthritis (RA) for more than 30 years. MTX has the highest 5-year retention rate of all disease-modifying antirheumatic drugs (DMARDs) at approximately 50% [1], [2], [3], and is generally effective in the long-term control of RA (up to 12 years) [4], [5]. Generally, 13–68% of early, untreated patients with RA who are naïve to DMARDs achieve clinical remission [defined as a DAS28 (Disease Activity Score including 28 joints) < 2.6 or DAS44 (including 44 joints) < 1.6) within 6 to 12 months of receiving MTX treatment [6], [7], [8], [9], [10], [11], [12], [13].

In 2013, the European League Against Rheumatism (EULAR) released updated recommendations on the use of synthetic and biologic DMARDs in the management of RA [14]. The important overarching principles associated with these recommendations suggest that rheumatologists should consistently aim for the best care possible, while considering individual and societal medical costs. In accordance with these principles, the recommendations support the continued role of MTX as the cornerstone of treatment, and state that MTX should be part of the first-line strategy in patients with active RA [14]. Furthermore, the recommendations also suggest that patient monitoring should occur often, with frequent adjustment in therapy to achieve the target of disease remission or of low disease activity state (LDAS) [14]. A switch from oral to parenteral MTX, including subcutaneous (SC) MTX, may enable more patients to achieve a disease remission without having to add a biologic [15], consistent with EULAR recommendations.

Clinically effective doses of MTX at 25–30 mg per week may be difficult to achieve using oral administration because of limitations in systemic exposure and tolerability. The bioavailability of oral MTX varies widely among individual patients and diminishes as doses increase [16], [17], [18]. At doses of 15 mg or higher, the bioavailability of oral MTX appears to plateau [19] and the absorption of oral MTX decreases by as much as 30%, most likely because of saturation of receptors in the proximal intestine [17], [20]. Furthermore, gastrointestinal (GI) side effects, such as nausea, abdominal pain, and diarrhea, are a frequent cause of oral MTX therapy discontinuation [3], [21].

Guidelines from other European rheumatology societies have also recommended a switch from oral to parenteral MTX as part of the management of RA [22], [23], [24], [25], [26]. A retrospective, controlled, population-based, observational study from the United Kingdom assessed the efficacy of SC MTX in patients who had an inadequate response to oral MTX therapy [27]. Overall, 29% of the patients who switched to SC MTX achieved LDAS (DAS28 < 3.2), compared with 16% of those treated with continuous oral MTX (P = 0.02) [27].

While several studies have examined the clinical benefit of switching from oral to SC MTX, fewer studies have examined the clinical efficacy and safety of SC MTX in MTX-naïve patients. A 6-month, multicenter, randomized, double-blind, controlled, 2-arm, phase 4 head-to-head trial involving 384 patients with active RA compared the clinical efficacy and safety of SC and oral MTX, and suggested that the use of SC MTX was significantly more effective than oral MTX, with no differences in tolerability [28]. However, the real-world use of SC MTX in MTX-naïve patients has not yet been explored in the context of treatment optimization strategies in the current EULAR recommendations.

To assess the efficacy, tolerability, and safety of SC MTX in MTX-naïve patients with RA under real-world clinical circumstances, a retrospective systematic analysis of the St. Gallen cohort’s patient records was conducted. Consistent with recommended treatment strategies from EULAR, patients were monitored frequently, SC MTX doses were escalated when needed, and biologic DMARDs were initiated if patients failed to achieve an adequate response using optimized doses of SC MTX.